266. Multiple Myeloma

Question 1

Plasma Cells

• Two specific IHC markers
• Difference between B Cells and Plasma Cells
• Normal Kappa:Lambda ratio

Answer 1

CD38, 138
B Cells: IgG on surface of cell
Plasma Cell: IgG cytoplasmic and secreted
K:L 2:1 (use to ID monoclonal proliferations)

Question 2

Define Plasma Cell Neoplasm

Define Monoclonal Gammopathy
- major lab finding

Distinguish MGUS and MM

Answer 2

PCN: uncontrolled growth/expansion of single clone of plasma cells, NOT sufficient for MM dx

MG: monoclonal Ig in blood or urine id’ed by SPEP (not always IgM) - causes M spike

MGUS: monoclonal expansion (<10% plasma cells in marrow) but ASX, most common plasma cell disorder (1-2% progress to MM per year)

MM: bone marrow-based malignant proliferation of plasma cells (10-60%) with evidence of ORGAN/TISSUE DAMAGE

Question 3

MM

• dx criteria
• demo
• bone marrow finding, stain

Smoldering Myeloma

• define
• complication

What is the pathophysiology of bone destruction in MM?
What factor produced by Myeloma Cells drives their growth?

Answer 3

MM
- CRAB (HyperCa, Renal insufficiency, Anemia, Bone Lesions (osteoLytic)
- dmo: peaks 65-70yo
- bone marrow: hypercellular, with more plasma cells, CD138+, abnormal light chain IHC (monoclonal proliferation), Dutcher bodies (intranuclear) and Russel Bodies (intracytoplasmic) - aggregations of IgG
- flow cytometry: CD38+, CD138+
Bone Destruction: Myeloma cells produce factors driving bone destruction! (activate RANKL)
Makes IL-6: MM cells dependent on it for growth, survival, Ig Production

Smoldering Myeloma: malignant proliferation of plasma cells (10-60%) with monoclonal Ig, but NO EVIDENCE of organ/tissue damage; 75% progress to sx MM

Question 4

What are the most common Ig’s in MM?

What are the consequences of monoclonal Ig’s in MM? (2)

Answer 4

IgG (55%), IgA (25%)

1. Nephrotoxic (Bence Jones Proteinuria = excretion of excess light chains in urine)
2. Primary Amyloidosis: misfolded monoclonal light chains form Beta-pleated sheets and deposit in extracellular tissue = nephrotic syndrome; Congo Red Stain shows APPLE GREEN BIREFRINGENCE

Question 5

Clinical Findings in MM

• CBC (2) - causes of both abnormalities
• 4 other key sx in MM (CP)
• complication of monoclonal Ig

Prognosis of MM
- factors influencing (5)

Answer 5

CBC: Anemia (due to bone marrow suppression and renal failure - less EPO), Rouleaux Formation (cells stack like coins due to serum Ig’s altering negative charge of RBCs)

• HyperCa due to bone destruction
• Bone lytic lesions = pathologic fractures in axial skeleton (vertebrae) and skull
• Renal insufficiency = light chain deposition in kidney
• Amyloidosis: renal and other organ failure
• Monoclonal Igs = state of hypogammaglobinemia (nonfx Igs) = INFECTION (most common cause of death in MM)

Prognosis: variable survival depending on:

1. Stage
2. Pt Factors (age, comorbidities)
3. Tumor Biology (cytogenetic studies, p53 loss is a big one)
4. Response to tx

Question 6

what is the tx for MM?

Answer 6

1. High dose combination chemotx with autologous stem cell tx followed by maintenance therapy
   - Proteasome inhibitors
   - Alkylating Agents (cytotoxicity)
   - Bisphosphonates (inhibit bone resorption - sx tx)
   - mab against CD38 (Daratumumab)

Question 7

Define Solitary Plasmacytoma, Primary Amyloidosis, Waldenstrom’s Macroglobulinemia

Answer 7

Solitary Plasmacytoma: only one lesion

• Of bone: 50% have gammopathy, 2/3 progress to MM
• Extramedullary: usually in upper respiratory site, 60-80% can be CURED, infequent progression to MM

Primary Amyloidosis: deposition of Ig Light Chains forming beta-pleated sheets into various tissue

• with or without MM
• if not MM, no monoclonal Ig

Waldenstrom’s Macroglobulinemia

• IgM monoclonal gammopathy (rare in MM) in presence of lymphoplasmacytic lymphoma
• IgM pentamers cause serum hyperviscosity: bleeding (platelet dysfx), NO lytic bone lesions